Targeting Glycans Puts Icing on T Cell Therapy

    Making a good thing even better, scientists based at the University of Pennsylvania School of Medicine have genetically modified T cells that show promise against solid tumors, not just blood cancers. To date, T cells modified to express chimeric antigen receptors (CARs) have been too indiscriminate to use against solid tumors. The CAR T cells would home in on cell-surface proteins that are common to both tumors and healthy tissues, causing serious side effects.

    Better-targeted CAR T cells, however, have been demonstrated in a preclinical study led by Laura Johnson, Ph.D., and Carl June, M.D., researchers affiliated with the University of Pennsylvania’s Center for Cellular Immunotherapies. In this study, CAR T cells were engineered that could be aimed at a very particular target: a sugar modification. More specifically, this is a truncated carbohydrate molecule, which is a Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers.

    To hit this target, the researchers armed CAR T cells with a monoclonal antibody called 5E5. When 5E5-equipped CAR T cells were injected into mice with leukemia or pancreatic cancer, the tumors shrank and were even eliminated in most animals, resulting in increased survival. The mice with pancreatic cancer were still alive 113 days after treatment with the CAR T cells; however, only one-third of the animals treated with CAR T cells that did not target the MUC1 proteins with the truncated carbohydrate survived until the end of the experiment. Importantly, the CAR T cells could not damage normal human cells or cells without the abnormal carbohydrate.

    These findings appeared June 21 in the journal Immunity, in an article entitled, “Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.” The article asserts that abnormal self-antigens can serve as targets for tumor rejection.

    “We develop and characterize a novel CAR based on a monoclonal antibody (5E5) specific to a Tn-MUC1 glycopeptide epitope widely expressed by adenocarcinomas,” wrote the article’s authors. “This CAR is able to eliminate Tn-MUC1-expressing tumors in mouse models of leukemia and pancreatic cancer. We propose that cancer-specific neoepitopes formed by aberrant glycosylation might serve as targets for CAR T cell therapy for a variety of adenocarcinomas and bone-marrow-derived cancers.”

    “We engineered T cells to target a cancer-associated surface protein with shortened carbohydrate molecules,” said the study’s first author Avery Posey, Ph.D., an instructor in Pathology and Laboratory Medicine. “Future cancer immunotherapies combining the targeting of cancer-specific carbohydrates and cancer proteins may lead to the development of incredibly effective and safe new therapies for patients. These engineered cells will be able to increase cancer specificity of this immunotherapy and decrease the potential for toxicity in patients.”

    The downside, Johnson cautioned, is that this type of therapy is still very new, and there are numerous factors that are involved at the tumor level that may limit treatment. In particular, more work is needed to determine the safety of this therapy in advanced mouse models that can more accurately predict safety in humans, and its efficacy specifically against metastatic cancer, which is the leading cause of cancer-related deaths. “So while we are hopeful,” noted Dr. Johnson, “no one ever knows if a cancer treatment is truly going to work, and be safe, until it actually goes to treat patients in the clinic.”

    If these preclinical studies are successful, the researchers plan todevelop their CAR T cell therapy further and test its safety and efficacy for different types of metastatic cancer in upcoming clinical trials.